Effect of omeprazole on oral and intravenous RS-methadone pharmacokinetics and pharmacodynamics in the rat

The effect of omeprazole on oral and intravenous (iv) RS-methadone pharmacokinetics and pharmacodynamics was studied in awake, freely moving rats, which were divided in four groups: oral RS-methadone (3 mg/kg) was given (a) to a control group (COoral) (n = 65) and (b) to an omeprazole pretreated group (OPoral) (n = 77), and iv RS-methadone (0.35 mg/kg) was administered (c) to a control group (COiv) (n = 86) and (d) to an omeprazole pretreated group (OPiv) (n = 86). Omeprazole (2 mg/kg) was given iv 2 h before RS-methadone. Plasma concentrations of RS-methadone (Cp) were determined by high-performance liquid chromatography and analgesic response by tail flick for 0-180 min (oral) and 0-120 min (iv). RS-Methadone rate of absorption (mean SE) was faster in OPoral (k(01) = 0.31 +/- 0.04 min(-1)) than in COoral (k(01) = 0.05 +/- 0.007 min(-1)), consequently plasma peak concentrations (C-max) were greater (197.41 +/- 33.70 ng/mL versus 83.54 +/- 7.97 ng/mL) and the time to reach C-max (t(max)) was shorter (11.23 +/- 1.32 min versus 39.18 +/- 1.74 min). Mean area under the Cp-time curve (AUC(0-infinity)) and hence bioavailability of oral RS-methadone were increased by omeprazole without significant changes in the elimination. Omeprazole did not affect the pharmacokinetics of iv RS-metbadone. The changes of the analgesic effect of RS-methadone as a function of time were similar in all four groups. In the COoral group, Cp and analgesic effect were defined by the E-max model. The relationship between Cp and drug effect in the OPoral group showed a counterclockwise hysteresis (k(e0) of 0.018 +/- 0.006 min(-1)). For the iv groups (COiv and OPiv), the Cp-analgesic effect relationship was described by an E-max sigmoid model and omeprazole did not affect the pharmacodynamic parameters. It is concluded that omeprazole causes an increase in the bioavailability of oral RS-methadone without modifying the analgesic response but affecting the Cp-effect relationship. (C) 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association.